Poly(ADP-ribose)polymerase, PARP, is also known as poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADPRT) and is one of key nucleus enzyme families present in eukaryotic cells. Up to date, it has been confirmed that the PARP nucleus enzyme family has 18 members, in which the most abundant member of PARP-1 functions more than 90% of the ribose diphosphate polymerization.
The structure of another member of this family PARP-2 is most similar to that of PARP-1. Both structures comprise three regions: one region is a DNA binding and nucleic aid orientation region comprising two “zinc finger” structures, which recognizes the damages of DNA by the zinc finger structures; the second region is central self-modifying region comprising 15 highly conservative glutamic acid residues, which is considered as a target of ribosylation of poly(ADP-ribose); and the third region is C-terminated region comprising NAD bonding sites and catalytic sites for synthesizing poly(ADP-ribose). The content of PARP is quite abundant in cells of the human body, especially in immunocytes and germ cells. The poly ADP ribosylation occurs in many physiological processes, leading to multiple effects, which include chromatin degradation, DNA replication, repair of DNA, genes expressions, division and differentiation of cells and apoptosis.
PARP also modulates expressions of various proteins including NO synthetase which mediates inflammation at transcriptional level. PARP, as a sensor for damages of DNA single- or double-strands, plays an important role in response to damages of DNA. When the double- or single strands of DNA breaks due to the effects such as radiation, oxidant and alkylating drugs, the activity of PARP significantly increases. Once the PARP is activated, the PARP cuts NAD into nicotinamide and ADP ribose, and polymerizes the latter onto nuclear receptor proteins including histone, transcription factor and PARP to form an adenosine diphosphate ribose polymer (PAR) similar to nucleic acids. The formation of the polymer with highly negative charges results in static pulse between DNA and histone and loose of the structure of chromatin. It is advantageous for recombination of chromatin, repair of DNA and modulation of transcription. It results in invasion of DNA repair enzymes such as XRCC1, LIGHIII, and the like, which is a key step in mechanism of DNA repairing.
Poly(ADP-ribose)polymerase plays two major opposite roles in response to DNA damage: PARP is one important factor for cell survival and maintaining the chromosome stability; on the other hand, the excessive activation of this enzyme is one of the important cause for apoptosis. The main reason causing the contradictory resides in that the external stimulates (such as alkylating reagents, rays, oxidation and others) cause different levels of DNA damages. When the DNA is slightly damaged, PARP is activated and repairs the damaged portions. When the cells are significantly damaged, PARP is largely activated and consumes a large number of NAD and further exhausts ATP in cells, such that the cells are in the state of energy deficiency and suffer more and unrepairabe damages, which result in necrosis or apoptosis of cells.